Ovulation is a complex, inflammation-like process whereby a fully-developed follicle ruptures in response to the actions of the mid-cycle gonadotropin surge, releasing the cumulus-oocyte complex (COC) for passage into the reproductive tract and possible fertilization. Shortly before ovulation, the luteinizing hormone (LH) surge induces processes critical for fertility, including cumulus-oocyte expansion (C-OE) and resumption of meiosis. While some of the paracrine-acting factors important for these events have been identified, the molecular mechanisms responsible for initiating such complex processes are not fully understood. Limited published studies and the PI's preliminary findings support a novel role for chemokine regulating events necessary for C-OE and oocyte maturation. Rodent studies suggest that chemokine signaling regulates the assembly of the cumulus extracellular matrix and thus fertilization. The PI's preliminary results from domestic cats demonstrated that the chemokine MCP-1 and its receptor (CCR2) are expressed in the oocyte and cumulus cells of COCs from small antral follicles. Similar results were observed in the monkey COC from small antral and preovulatory follicles. Moreover, MCP-1 and CCR2 mRNA increased in the preovulatory follicle 12 hr after an ovulatory stimulus with MCP-1 returning to pre-hCG levels at 24 and 36 hr. MCP-1 protein content in the follicular fluid paralleled the mRNA levels and peaked at 12 hr post hCG, notably the period of time that is just prior to the initiation of events necessary for C-OE and the resumption of oocyte meiosis in the rhesus preovulatory follicle. Based on these findings, we hypothesize that chemokines that interact with the chemokine receptor CCR2 (e.g. MCP-1) have a direct effect on promoting C-OE and/or oocyte maturation. Therefore, to test this hypothesis experiments are designed to: 1) Evaluate LH-dependent regulation of chemokines and their receptors in preovulatory follicles, 2) Assess the effects of CCR2 signaling on the regulation of molecular events necessary for C-OE and/or oocyte maturation, 3) Determine whether the inhibition of CCR2 signaling in the COC prevents C-OE and/or oocyte maturation. The project will be developed in a feline model, which has the advantage of providing an excellent surrogate for understanding events the human COC that are necessary for fertility;as cat oocytes share several characteristics with human oocytes. The cat also provides a unique and valuable model to study molecular processes within the preovulatory follicle and COC, due to the fact that each animal provides between 3 to 7 preovulatory follicles, naturally selected in an "ovulation-ready" state waiting for the LH stimulus during estrus, providing a window of approximately 7 days that sample can be collected. Therefore, these novel and innovative studies will aid in increasing our understanding of events required for fertilization, thereby leading to the identification of novel non-hormonal targets for contraception as well as identification of possible cause of infertility and/or good molecular markers for oocyte quality.

Public Health Relevance

Ovulation is a complex, inflammation-like process whereby a fully-developed follicle ruptures in response to the actions of the mid-cycle gonadotropin surge, releasing the cumulus-oocyte complex (COC) for passage into the reproductive tract and possible fertilization. The goal of this project is to study the role of chemokines in regulating such events.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Research Project (R01)
Project #
1R01TW009163-01A1
Application #
8409743
Study Section
Special Emphasis Panel (ZRG1-BDA-Q (55))
Program Officer
Michels, Kathleen M
Project Start
2013-08-01
Project End
2017-04-30
Budget Start
2013-08-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$45,000
Indirect Cost
$3,333
Name
Center/ Endocrinological Investigations
Department
Type
DUNS #
971340870
City
Buenos Aires
State
Country
Argentina
Zip Code
C1425-EFD